The Mechanism of Markovnikov-Selective Epoxide Hydrogenolysis Catalyzed by Ruthenium PNN and PNP Pincer Complexes

The homogeneous catalysis of epoxide hydrogenolysis to give alcohols has recently received significant attention. Catalyst systems have been developed for the selective formation of either the Markovnikov (branched) or anti-Markovnikov (linear) alcohol product. Thus far, the reported catalysts exhibiting Markovnikov selectivity all feature the potential for Noyori/Shvo-type bifunctional catalysis, with either a RuH/NH or FeH/OH core structure. The proposed mechanisms of epoxide ring-opening have involved cooperative C–O bond hydrogenolysis involving the metal hydride and the acidic pendant group on the ligand, in analogy to the well-documented mechanism of polar double-bond hydrogenation exhibited by catalysts of this type. In this work, we present a combined computational/experimental study of the mechanism of epoxide hydrogenolysis catalyzed by Noyori-type PNP and PNN complexes of ruthenium. We find that, at least for these ruthenium systems, the previously proposed bifunctional pathway for epoxide ring-opening is energetically inaccessible; instead, the ring-opening proceeds through opposite-side nucleophilic attack of the ruthenium hydride on the epoxide carbon, without the involvement of the ligand N–H group. For both catalyst systems, the rate law and overall barrier predicted by density functional theory (DFT) are consistent with the results from kinetic studies.

grid was used for all calculations, which aided convergence of structures with loosely bound fragments such as explicit isopropyl alcohol molecules. Complete structures with no truncations were used in all cases. Geometry optimization and frequency calculation were conducted in solvent, using a polarizable continuum with radii and non-electrostatic terms from Truhlar and coworkers' SMD solvation model, and with dielectric constants chosen for 2-propanol. 5 Geometry optimization in solvent is important to identify ion-pair intermediates that might be missed in the gas phase. 6 However, convergence is occasionally problematic. In difficult cases, we repeated the calculations using different, nearly converged starting points, each time with a fresh calculation of the force constants, using a range of values for the maximum step size. Despite this effort, convergence in solvent was not successful for RuO i Pr-solv PNN and a-TS PNN . For these structures, the geometry optimization and frequency calculation used for free-energy corrections were done in the gas phase at the same B97X-D/def2-SVP level described above, and a single-point electronic-energy refinement at the B97X-D/def2-TZVP level was conducted using the solvent model.
Frequency calculations ensured the absence of imaginary vibrational modes in intermediates and the presence of exactly one imaginary mode in transition states. Intrinsic reaction coordinate calculations were employed to verify that transition states led to the specified minima. Free-energy corrections were calculated at the experimental reaction temperature of 83 °C, or 356.15 K. Standard state corrections were added in order to adjust from 1 atm to 1 M for solution-phase free energies, amounting to 2.39 kcal/mol added to the free energy of each isolated molecule at 356.15 K. 7 Although the standard state for molecular hydrogen is sometimes taken as the gas at 1 atm, we have used a 1 M standard state in 2-propanol, for consistency in computing reaction kinetics from the calculated free energies. The solvation-corrected electronic energies were further refined using the same B97X-D functional and the larger basis set def2-TZVP. 4 All free energies reported in the paper refer to 1.0 M standard concentrations at 356.15 K. A table of energies is provided in the Supporting Information, and geometries in Cartesian coordinates are included in a separate, compiled .XYZ file. The .XYZ file also contains the single imaginary frequency for all transition states identified.
To assess the dependence of the calculated energies on the selected density functional, we have recalculated electronic single-point energies using the same def2-TZVP basis set and three additional functionals: B3LYP-D3 8 (applying Grimme's D3 dispersion correction), 9 M06L, 10 and MN15. 11 Table S2 shows the effect of functional choice on the relative free energies. Broadly, the effect of functional choice is minimal and does not change the key conclusions regarding the overall catalytic barriers or the identities of turnover-frequency-determining species.
Consideration of potential TDIs, including explicit solvation. In the early stages of the development of the MEPs shown in Figure 2 in the main text, we compared the free energies of plausible catalyst resting states. Figure S1 below shows the relative free energies of alkoxide RuO i Pr, unsaturated species c-nosolv, and hydride RuH for the RuPNP and RuPNN systems. In a previous study on the mechanism of ester hydrogenation catalyzed by RuH PNN , we found it essential to consider an additional hydrogen-bonded alcohol molecule to correctly model catalyst speciation. 1b For each intermediate in this work, we considered the effect of including a molecule of 2-propanol, the optimal solvent for the reaction and the hydrogenation product for our model substrate, propylene oxide. We note that for the RuPNN system, convergence of RuO i Pr-solv in continuum solvent was unsuccessful despite multiple attempts. This species was optimized in the gas phase, and the gas-phase free-energy correction was applied to the single-point electronic energy calculated using continuum solvent. Each species (RuO i Pr-solv, c, and f) shows a small (≤3.1 kcal/mol) effect of adding an explicit hydrogen-bonded 2-propanol molecule. This contrasts with our previous study, which showed that an explicit ethanol molecule stabilized the ethoxide intermediate analogous to RuO i Pr by 7.4 kcal/mol, resulting in an alkoxide resting state for that system. This difference can be rationalized by considering the solvents used: the prior study employed toluene in both the computational and kinetic studies, while the present study employs 2-propanol as solvent. In the more polar 2-propanol solvent model, the inclusion of explicit hydrogen bonding has a smaller effect on the calculated energies. Because none of the 2-propanol adducts RuO i Pr-solv, c, and f were significantly more stable than their unsolvated counterparts RuO i Pr, c-nosolv, and RuH, the 2-propanol adducts were not considered in the kinetic modeling described later. Note that, as shown in Figure 2, c rather than c-nosolv lies on the MEP because hydrogen activation is substantially facilitated by an alcohol proton shuttle. For both the RuPNP and RuPNN systems, we find that the hydride species RuH is the most stable at the 1 M standard state. The unsaturated species c-nosolv is high enough in energy that it does not represent a significant fraction of the resting speciation for either catalyst. In the RuPNP system, the alkoxide species RuO i Pr also represents a minor component in catalyst speciation, so the hydride RuH can be considered to be the dominant resting state and the sole turnover frequency-determining intermediate (TDI). The situation is potentially more complicated for the RuPNN system because of the lower free energy of the alkoxide intermediate RuO i Pr PNN . Assuming a fast equilibrium under catalytic conditions, the calculated free energy difference of 6.6 kcal/mol between RuO i Pr PNN and e corresponds to an RuO i Pr PNN : RuH PNN ratio of 1:99, given a neat molarity of 13.1 M for 2propanol and a hydrogen solubility of 0.093 M at 20 bar and 83 °C (see Equation S1 below). However, if the free energy difference were overestimated by the DFT method, RuO i Pr PNN would represent a greater fraction of the resting catalyst speciation. Figure S2 shows the predicted fraction of RuO i Pr PNN as a function of its free energy relative to RuH PNN under these conditions. If RuO i Pr PNN lies above RuH PNN by only 3.5 kcal/mol for example, a 1:1 ratio of the two species is expected. In this regime, the steady-state concentration of e is expected to be influenced by the hydrogen concentration, which would result in saturation kinetics, as derived on page S14.
(S1) RuO i Pr PNN Figure S2. Predicted fraction of RuO i Pr PNN as a function of its free energy relative to RuH PNN .
Alternative pathways: Hydrogen activation without a proton shuttle. In the MEPs shown in Figure 2, hydrogen activation is assisted by a molecule of 2-propanol, giving a relative TS free energy of 22.6 kcal/mol for the RuPNP catalyst and 19.1 for the RuPNN catalyst. For comparison, we calculated the analogous pathways without a proton shuttle and find higher barriers. Figure S3 shows these sequences, with the RuPNP system in red and the RuPNN system in black. Without a proton shuttle, we find significantly higher barriers of 32.2 kcal/mol for the RuPNP system and 28.8 kcal/mol for the RuPNN system. Figure S3. Hydrogen activation without a proton shuttle. The RuPNP pathway is shown in red and the RuPNN pathway is shown in black. Free energies are in kcal/mol against the hydride resting state RuH.
Alternative pathways: Epoxide ring-opening including an explicit solvent molecule. In the MEPs shown in Figure  2, epoxide ring-opening is modeled without an explicit solvent molecule. Because the epoxide oxygen is developing a negative charge in h-TS, we considered that an explicit 2-propanol might be necessary to properly model this species. Figure S4 shows the epoxide ring-opening sequence for the RuPNN system with an isopropanol molecule included to stabilize the developing negative charge on the oxygen atom. The relative free energy of h-TS-solv PNN is 31.0, which can be compared with the free energy of 25.1 for h-TS PNN , the analogous TS lacking an explicit solvent molecule. Figure S4. Epoxide ring-opening pathway for RuPNN system, including an explicit 2-propanol molecule to stabilize the developing negative charge on the epoxide oxygen.
Energies Calculated by DFT. Table S1 below shows the energies calculated by DFT for all structures reported in this paper. The column E(BS2) represents the solvent-corrected electronic energy in hartrees, calculated with the B97X-D functional and the def2-TZVP basis set. The column G(corr) represents the correction to the Gibbs free energy calculated at 356.15 K after geometry optimization using the B97X-D functional and the def2-SVP basis set. The column SS G (kcal) represents the Gibbs free energy for each isolated species at 356.15 K in kcal/mol, including the addition of 2.39 kcal/mol for each molecule to convert to a 1 M concentration. The column Mass Balance lists the small molecules included in the total free energy for the calculation of reaction pathways. The column G(total, kcal) is the sum of free energies of the ruthenium complex and any small molecules included for mass balance. The column G(rel) is the total free energy referenced against e with the organic reactants. Table S2 shows the solvent-corrected single-point electronic energies calculated by DFT using B97X-D in addition to three other density functionals for comparison: B3LYP-D3, M06L, and MN15 (left), along with the relative free energies for each functional. All free energies employ the same free-energy correction calculated at the B97X-D/def2-SVP level as described above.  Apparatus for kinetic experiments. Kinetic experiments were conducted in an Asynt Multicell Parallel High-Pressure Reactor, designed to allow sampling of aliquots from five hydrogenation reactions run in parallel. Our customization of this apparatus was described previously, 1a but is repeated here for convenience. The reactor was customized to fit in our glovebox antechamber and to include reaction sampling valves on five reactor cells. The sampling valves employ 0.8 mm ID 1/16" stainless steel tubing, a Swagelok Low Flow metering valve (part no. SS-SS1) to control flow, and a Swagelok ball valve (part no. SS-41GS1) to allow removal of samples. As the internal volume of the sampling valve system was measured to be 0.25 mL, removal of 0.50 mL of liquid before collecting each aliquot ensures that a fresh sample was being taken directly from the reaction mixture. A sixth reactor cell is fitted with a thermocouple to allow control of the internal reaction temperatures. For heated reactions, the reactor was partially submerged (2 cm past the internal liquid level) in a stirred oil bath (a non-magnetic stainlesssteel cooking pot), whose temperature is controlled using heating tape (Briskheat part no. BIH051040L) wrapped around the oil bath and an Omega Platinum Series Universal Benchtop Digital Controller, part no. CS8DPT. The oil bath is placed on a stirring hotplate, which allows stirring of the reactions and oil bath, as well as pre-heating of the oil to allow the reactions equilibrate to the desired temperature quickly.
Experimental procedure for kinetic experiments. First, the oil bath was preheated to an empirically determined temperature above the desired reaction temperature to enable rapid equilibration to the desired temperature (90 °C for the 83 °C reactions described in this work). The Asynt reactor was brought into the glovebox with ovendried glass reactor liners and Teflon-coated stir bars. Reaction solutions, with a total volume of 10.0 mL, were prepared with the appropriate amount of ruthenium complex, epoxide, and tetradecane (0.20 equiv. relative to epoxide) as internal standard. The reactor was closed and removed from the glovebox and allowed to incubate for 20 minutes in the water bath. After gently purging the H2 line for 3 minutes, the reactor was pressurized to bar the desired pressure. The thermocouple was connected to the Omega temperature controller, and the reactor was submerged in the pre-heated oil bath with stirring set to 500 rpm. The internal reaction temperature was recorded each minute until it was stable, and time zero was marked when the temperature was 5 °C below the target temperature. Typically, the warmup time was 5-10 minutes. Aliquots were removed at predetermined times for analysis by gas chromatography. To ensure that samples represented the reaction mixture without contamination from the transfer line, 0.5 mL of reaction mixture was discarded before one drop was collected for each aliquot. Each one-drop aliquot was diluted with 1 mL toluene in a crimp-top vial, then sealed and analyzed by GC-FID. The concentrations of reactant and products at each time point were determined by integration of their GC signals against the tetradecane standard. GC analysis employed a Shimadzu SH-Rxi-5ms column 15 meters in length. The oven temperature was initially held at 50 °C for 3 minutes, then increased to 250 °C at a rate of 20 °C/min, then held at 250 °C for 2 minutes. With these parameters, tetradecene oxide eluted at 10.09 minutes, 2-tetradecanol eluted at 9.98 minues, 1-tetradecanol (less than 1% of the product) eluted at 10.38 minutes, and the standard tetradecane eluted at 8.67 minutes. The concentrations measured over time in these experiments are reported in the tables below.  In integrated form, the rate law is: The rate constant k can be calculated in each experiment as: Table S5 below shows this analysis for the seven kinetic experiments involving Ru-MACHO-BH as precatalyst.

Determination of the rate law and activation barrier for the RuPNN catalyst.
If the dihydride species RuH PNN were the sole TDI, the same rate law described above for the RuPNP system would apply to the RuPNN system. If the alkoxide intermediate RuO i Pr PNN is close enough in free energy to occupy a significant fraction of the ruthenium speciation under catalytic conditions, a more complicated rate law will apply, as determined by the sequence shown in Scheme 2 in the main text. In the following derivation, we have assumed that the hydrogenolysis product 2-tetradecanol will interact with the ruthenium species similarly to the 2-propanol solvent. Since the solvent at 13.1 M is always at a much higher concentration than the product, we have ignored the 2-tetradecanol product in the kinetic analysis.
The two-step sequence in Scheme 2 can be written in linear form as: Here, we can make a simplifying assumption that k 2 [epoxide] is negligible in the denominator. If k 2 [epoxide] were significant, saturation behavior in [epoxide] would be observed at high epoxide concentrations. This assumption is also consistent with the energy barriers predicted by DFT. The barrier from RuH PNN to h-TS PNN (corresponding to k2) is 25.1 kcal/mol, while the barrier from RuH PNN backwards to e-TS PNN Figure S5 below shows the plot of k obs [Ru total ] vs [H2]. The gray line represents a least-squares fit, where K1 = 96.5 ± 35.1 and k2 = 0.461 ± 0.093 M -1 ·s -1 . Figure S5. Determination of K1 and k2 for the RuPNN system.
Using the equation G° = -RT ln K at the reaction temperature of 356.15 K, we find that G° for reaction 1 is -3.32 ± 0.26 kcal/mol. Using the Eyring equation, we find that G ‡ for reaction 2 is 21.52 ± 0.14 kcal/mol.